Hereditary hemochromatosis (HH) is the most common inherited disorder in people of Northern European origin. Iron overload results in damage specific organs leading to cirrhosis of the liver, liver cancer, diabetes, cardiomyopathy, and arthritis. The liver is a major iron-sensing organ in the body. Transferrin is the major iron transport protein in the blood. Mutations in transferrin receptor 2 (TfR2), which is predominantly expressed in hepatocytes and erythrocyte precursors result in HH. Tfr2 forms a complex with HFE, another protein involved in iron homeostasis. Experiments described in this proposal will test the model that the TfR2-HFE complex provides a sensing mechanism to detect iron-loaded Tf and thereby regulates the transcription of hepcidin, a peptide hormone that negatively regulates the efflux of iron out of intestinal cells and macrophages. Alternatively, the TfR2-HFE complex could establish basal levels of hepcidin transcription. Other proteins involved in the complex and in signaling mechanisms will be identified. The long-term goal of this research is to understand how mutations in key proteins disturb the iron balance in the body to reveal the mechanisms by which the body regulates iron-homeostasis.